A distinctive event in neoplasia is the appearance of new, normally repressed, modified or conformation perturbed molecular species on the surface of tumor cells. These events present potentially new antigenic sites, neoantigens, by which cellular and humoral immunity may be invoked by the host and immunological surveillance mediated. Such neoantigens may be employed as discriminating markers for molecular and cellular events associated with neoplasia including gene derepression, oncogenic virus infection, organizational changes of the cell surface that may reflect transformational events. Precisely defined tumor- associated neoantigenic markers also may be utilized in a pragmatic fashion for the diagnosis of neoplasia as well as in potential future immunotherapeutic approaches to cancer. An as yet incompletely defined and established neoantigenic marker of neoplasia of the gastrointestinal tract of man is the so- called "carcinoembryonic antigen" (CEA). We propose to isolate in very highly purified form each of the six or more CEA molecular variants present in gastrointestinal tumors. Each apparent CEA variant will be characterized by quantitative primary binding immunoassays in respect to specificity and number of sites per molecule, and characteristic antigen-dependent binding affinity. These CEA molecules will be degraded to constituent polypeptide chains, fragments, and carbohydrate moieties to identify the CEA determinant(s) per se. Tumor-association and significance in immunologic surveillance will be assessed by investigation of cell surface exposure, metabolic events regulating cell surface expression, lymphocyte-mediated cytotoxicity and antibody- mediated cytotoxicity on tumor and normal colonic epithelial cells. These studies should provide the scientific basis upon which to base precise and discriminating investigations of the immunobiology of cancer in man.